RESUMEN
Alzheimer's disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid ß (Aß), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TRKB) and increasing oxidative stress, caspase-1, and acetylcholinesterase (AChE) activities. Here, we have found the potential of two novel synthetic coumarin derivatives, ZN014 and ZN015, for the inhibition of Aß and neuroprotection in SH-SY5Y neuroblastoma cell models for AD. In SH-SY5Y cells expressing the GFP-tagged Aß-folding reporter, both ZN compounds reduced Aß aggregation, oxidative stress, activities of caspase-1 and AChE, as well as increased neurite outgrowth. By activating TRKB-mediated extracellular signal-regulated kinase (ERK) and AKT serine/threonine kinase 1 (AKT) signaling, these two ZN compounds also upregulated the cAMP-response-element binding protein (CREB) and its downstream BDNF and anti-apoptotic B-cell lymphoma 2 (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of ZN014 and ZN015. A parallel artificial membrane permeability assay showed that ZN014 and ZN015 could be characterized as blood-brain barrier permeable. Our results suggest ZN014 and ZN015 as novel therapeutic candidates for AD and demonstrate that ZN014 and ZN015 reduce Aß neurotoxicity via pleiotropic mechanisms.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Cumarinas/farmacología , Proteínas Fluorescentes Verdes/toxicidad , Fármacos Neuroprotectores/farmacología , Acetilcolinesterasa/metabolismo , Disponibilidad Biológica , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Caspasa 1/metabolismo , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Cumarinas/química , Técnicas de Silenciamiento del Gen , Humanos , Proyección Neuronal/efectos de los fármacos , Agregado de Proteínas , Especies Reactivas de Oxígeno/metabolismo , Receptor trkB/metabolismoRESUMEN
α-Halohydrazones/ketoximes are transformed into trisubstituted pyrazoles/disubstituted isoxazoles by treatment with phosphine, acyl chloride, and a base. Mechanistic investigations revealed the in situ formation of azo/nitroso olefin intermediates which underwent a tandem phospha-Michael/ N- or O-acylation/intramolecular Wittig reaction to afford the heteroarenes in moderate to good yields. Further, proper functionalization of α-haloketoximes and a change of conditions allowed the chemoselective synthesis of chromenone-oximes as well as rearranged isoxazoles, thereby realizing a diversity-oriented synthesis.